The present invention is directed to an drug-delivery tool and method of delivering selected therapeutic and/or diagnostic agents to target sites in selected body tissues. More particularly, the invention provides for the creation of temporary cavities in desired layers of a selected tissue, for example, myocardial tissue of the heart, and for the delivery of one or more selected agents therein.
Intra-muscular needle injection of therapeutic compounds is well known in the medical arts, as is intra-coronary injection where pre-existing intra-coronary arteries provide perfusate conduits. In heart disease, the existing coronary artery in-flows to capillary beds is often compromised. Newly developed gene and protein therapeutic agents hold promise in their ability to act on the surviving smaller capillary beds to grow and expand them. As has been witnessed, the intra-myocardial cellular lattice limits angiogenic response to about 5-10 mm and similar limits occur with direct needle injections in stunned or ischemic heart tissue. The physician must work within an environment of compromised capillary bed vascularity. Physicians are further limited to some degree by drug viscosityxe2x80x94where the drug viscosity is too low, rapid wash-out can occur; and where too high, capillary occlusion can occurxe2x80x94as well as by high infusate pressure induced cellular damages. These problems are not typical of common healthy muscle tissue injections in the arm or leg. The prior art teaches the creation of permanent channels with the use of lasers, radio frequency heating and mechanical cutting means. Such channels often compromise the capillaries that are sought to be accessed with a drug, wash out readily, and resolve ultimately as fibrous connective scar tissue. Needle and membrane tools may improve access to capillaries but offer no stretching forces and don""t offer unobstructed capillary access.
One embodiment of the invention provides a drug-delivery tool for delivering a drug to an internal member of a tissue, such as a heart-wall. The tool comprises an accessing device having distal and proximal ends, an inner lumen extending therebetween, a drug-delivery reservoir adapted to hold such drug, and a user-control structure at the accessing device""s proximal end. The tool further includes a tissue-penetrating implement carried at the accessing device""s distal end for axial movement into and out of the lumen. The implement has first and second expandable members which are disposed in a substantially co-extension condition, when the implement is disposed in a retracted condition within the lumen. Alternatively, the implement may assume an expanded, spaced-apart condition when the implement is advanced to an extended condition out of the lumen. At least one of the members has a tip for penetrating such tissue. A first operative connection exists between the control structure and the implement that is operable, upon user activation of the control structure, to advance the implement from its retracted to its extended condition. When the accessing device""s distal end is placed against a surface region of the tissue, the implement is advanced into the tissue, causing the two expandable members to expand to form a cavity within the tissue. A second operative connection exists between the control structure and the reservoir that is operable, upon user activation of the control structure, to deliver drug from the reservoir into such cavity. Placement of the accessing device""s distal end against a surface region of such tissue, and activation of the control structure results in the delivery of drug into a cavity within the tissue.
In another embodiment, the implement includes at least two expandable elements which move away from one another as the implement is being advanced, from its retracted to its extended condition, into such tissue, to form a cavity in the tissue.
In yet another embodiment, the second expandable member of the tissue-penetrating implement defines a lumen having a plurality of openings that permit direct communication of an drug passed into a cavity formed by the tool with at least about 90% of the surface area of the tissue directly bordering the drug receiving space.
In a particularly preferred embodiment, the accessing device is a flexible catheter accessing device; and further comprises a pull-wire assembly extending longitudinally through the catheter accessing device, the pull-wire assembly being is operable to deflect the distal end of the accessing device substantially within a plane; and one or more force contact transducers mounted at the distal end of the accessing device within the deflection plane. This embodiment may further comprise one or more additional force contact transducers mounted at the distal end of the accessing device outside of the deflection plane.
In another embodiment, the first expandable member further comprises construction from a shape memory material capable of a first remembered curved shape, and a second, stress induced linear shape causing the first expandable member to cut in an arc shape as it is advanced through a tissue upon extension from the confines of the accessing device lumen.
In still another embodiment, the second expandable member comprises a ribbed balloon, wherein each rib defines a lumen in fluid communication with the drug-delivery reservoir, and each rib further defines a plurality of exit ports from the rib lumen that the drug may perfuse through into the formed cavity.
In another embodiment, the first expandable member is formed in a cork-screw shape tubular member defining a lumen within exiting at an end distal to the accessing device and in communication with the drug-delivery reservoir, the first expandable member is rotatable along its axis to permit it to screw into a tissue upon axial rotation, and upon stopping axial rotation, withdraw into the lumen of the accessing device thereby pulling the tissue up into the lumen of the accessing device until such tissue is sealably urged against the accessing implement""s lumen edge causing a seal to form between the accessing implement""s lumen edge and the tissue, and further causing a cavity to form between the distal region of the first expandable member and the tissue adjacent to that region.
In one embodiment, some of the expandable members of the tissue-penetrating implement define lumens with a plurality of openings in fluid communication with the drug-delivery reservoir such that a drug may be introduced into a formed cavity with at least about 90%, and preferably greater than about 95%, of the surface area of the tissue directly bordering the cavity.
The accessing device can be, for example, a flexible catheter accessing device or the accessing device of an endoscope-type tool. In an embodiment of the former (i.e., a catheter-type tool), the tool further includes (i) a pull-wire assembly extending longitudinally through the catheter accessing device, with the pull-wire assembly being operable to deflect a distal-end region of the accessing is device substantially within a plane; and (ii) one or more (for example, two) ultrasound or force contact transducers mounted on opposing sides of the orifice at the distal end of the accessing device within the deflection plane. Optionally, one or more (for example, two) additional transducers can be mounted at the distal end of the accessing device outside of the deflection plane.
One aspect of the present invention provides an drug-delivery tool for delivering a selected diagnostic or therapeutic agent to a target site within a selected body tissue, such as myocardial tissue of the heart. Generally, the drug-delivery tool includes an accessing device having proximal and distal ends, with a lumen extending between such ends and terminating at an orifice at the distal end. A tissue-penetrating implement is movable between a retracted condition, within a distal region of the lumen, and an extended condition, extending out of the orifice. The tissue-penetrating implement includes a tip configured to penetrate a selected body tissue when (i) the distal end of the accessing device is placed thereagainst and (ii) the implement is advanced from its retracted condition to its extended condition. In addition, the tissue-penetrating implement includes a first expandable member, disposed proximal of the tip, for following the tip to a target site as the tip penetrates the selected tissue. A second expandable member, also proximal to the tip of the implement, is adapted to expand radially as the implement is advanced to its extended condition, with a force sufficient to form a cavity at the target site by pressing the tissue adjacent the penetration site away from the longitudinal axis of the implement. An agent-delivery passage or conduit extends longitudinally through at least a member of the accessing device, with a distal end of the passage defining an exit port facing the expandable member of the tissue-penetrating implement. By this construction, an agent, passed or drawn through the passage and out of the exit port, is directed into a central region of the expandable member, and any cavity formed thereby.
In one embodiment, the tissue-penetrating implement of the drug-delivery tool includes (i) a cutting or slicing tip at its distal-end region, and (ii) one or more resiliently flexible expandable members extending proximally therefrom, with the expandable members being adapted to expand radially outward in their normal state. The expandable members can be, for example, wires or filaments made of Nintinol, or the like. Movement of the tissue-penetrating implement can be effected using an actuation line attached at one end to a proximal end of the implement and attached at its other end to a manually operable deflection mechanism at a proximal end of the drug-delivery tool. By this construction, sliding movement of the line within the accessing device is transmitted to the implementxe2x80x94causing the implement to move.
The agent-delivery passage of the drug-delivery tool can be formed, for example, by an elongate conduit having an internal lumen that extends between the proximal end of the accessing device and a distal-end region of the accessing device. In one embodiment, such a conduit is adapted for sliding movement within the accessing device, coupled with movement of the tissue-penetrating implement.
One embodiment of the drug-delivery tool, particularly useful for delivering a selected agent having a net negative charge (for example, DNA), further comprises first and second electrodes adapted to be placed in electrical communication with a power supply. The first electrode, in this embodiment, is disposed at a distal region of the tissue-penetrating implement and the second electrode is disposed proximally of the implement. Generation of a positive charge at the first terminal is effective to draw at least a portion of the negatively charge species from a supply or holding reservoir, through the agent-delivery passage, and into the expandable member of the tissue-penetrating implement.
Another embodiment of the drug-delivery tool is particularly well suited for placing a solid or semi-solid agent in a cavity formed by the cavity forming implement, and then permitting the agent to move outwardly as portions of it dissolve or otherwise slough off. In one particular construction, the expandable member of the tissue-penetrating implement includes a plurality of resiliently flexible expandable members (for example, wires or filaments of Nintinol, or the like) disposed at spaced positions about the longitudinal axis of the implement so as to define a cage or skeleton capable of holding the agent as it is placed in a cavity formed by the implement. The cage is provided with open regions between its expandable members sufficient to provide direct exposure of the agent to at least about 95% of the tissue bordering the cavity.
Another general embodiment of the drug-delivery tool of the invention includes (i) an accessing device having proximal and distal ends, with a lumen extending therebetween and terminating at an orifice at the distal end; (ii) a tissue-penetrating implement movable between a retracted condition, within a distal region of the lumen, and an extended condition, extending out of the orifice; with the implement including (a) a tip configured to penetrate a selected body tissue when the distal end of the accessing device is placed thereagainst and the implement is moved from its retracted condition to its extended condition, and (b) a cage member disposed proximal of the tip for following the tip to a target site within such tissue, and adapted to assist in the formation and maintenance of a cavity at the target site by pressing the tissue at the target site away from the longitudinal axis of the implement as it is inserted therein and having sufficient rigidity to resist inwardly directed forces of the tissue tending to collapse the cavity; and (iii) an agent-delivery passage extending longitudinally through at least a member of the accessing device, with a distal end of the passage defining an exit port facing the cage member for directing a selected agent, passed through the passage, into a central region of the cage member and any such cavity formed thereby.
The cage member can comprise, for example, a plurality of expandable elements disposed about the central, longitudinal axis of the implement, with open regions between adjacent expandable members. Preferably, at least about 95% of the cage member is open. The cage member can be expandable (tending to flex outwardly), or generally non-expandable.
In another of its aspects, the present invention provides a method for delivering a selected diagnostic or therapeutic agent to a target site within a selected body tissue. According to one general embodiment, the method includes the steps of:
(i) forming a cut or slice extending from a wall of the selected tissue to the target site;
(ii) moving or pressing the tissue bordering the cut or slice radially outward, thereby forming a cavity within the tissue at the target site;
(iii) delivering a selected agent into the cavity, with the cavity being maintained; and
(iv) permitting the cavity to collapse once a selected amount of the agent has been delivered therein.
In one embodiment, at least about 90% (and preferably greater than 95%) of the surface area of the tissue bordering the cavity is directly exposed to the cavity, so that the agent delivered into the cavity can pass directly into the exposed tissue.
Step (i) of the method (i.e., cutting/slicing) is preferably effected using a cutting or slicing implement, such as a blade edge or tip, that is configured to avoid the removal of tissue along the region of the cut or slice beyond the inherent cellular injury due to the cutting or slicing.
According to one embodiment, the cut or slice formed in step (i) is made along a substantially linear axis, with the axis being oriented generally normal to the wall of the selected tissue. Ultrasound can be used to achieve such orientation.
The agent can be delivered using, for example, an elongate agent-delivery conduit defining a passage or lumen terminating at a distal orifice through which the agent can exit. Preferably, during delivery of the agent using such a tool, the orifice does not make substantial contact with the selected tissue, thereby maximizing the tissue surface area available for contact with the agent.
In one embodiment, the selected tissue is heart tissue (for example, myocardial tissue), and the cut or slice is formed from an endocardial wall, a septal wall, or an epicardial wall.
In another embodiment, the selected tissue is stunned, ischemic and/or hibernating organ tissue that has at least partially lost its normal capillary ability at vasomotion. The greater surface area and capillary access provided by practicing the present invention permits the agent to be moved through micro-capillaries even where assistance by natural vasomotion is greatly diminished or unavailable.
A wide variety of agents can be delivered using the present invention. The selected agent can be, for example, an angiogenic agent (for example, a protein and/or nucleic acid). In one embodiment, the agent is a nucleic acid, for example, naked DNA, intended for delivery to heart tissue.
A further aspect of the present invention provides a method where the normal pressure drug tissue treatment area of 5-10 mm obtained with direct needle injection or TMR can be improved upon by creating a temporary cavity having significantly greater direct capillary access due to surface area, lack of non-perfusing delivery implement to cell contact patches and implement stretching force.